Jonathan D. Rich

Inaccuracy of Doppler Echocardiographic Estimates of Pulmonary Artery Pressures in Patients With Pulmonary Hypertension: Implications for Clinical Practice

BACKGROUND Recent studies suggest that Doppler echocardiography (DE)-based estimates of pulmonary artery systolic pressure (PASP) may not be as accurate as previously believed. We sought to determine the accuracy of PASP measurements using DE compared with right-sided heart catheterization (RHC) in patients with pulmonary hypertension (PH). METHODS We compared DE estimates of PASP to invasively measure PASP during RHC in 160 consecutive patients with PH (part one). To account for possible changes in hemodynamics between DE and RHC, we then prospectively determined PASP in an additional 23 consecutive patients undergoing simultaneous RHC and DE (part two). Bland-Altman analyses were performed to evaluate the agreement between RHC and DE measurements of PASP. Accuracy was predefined as 95% limits of agreement within ± 10 mm Hg for PASP estimates. RESULTS In part one, there was moderate correlation between DE and RHC measurements of PASP (r = 0.68, P < .001). However, using Bland-Altman analysis, the bias for DE estimates of PASP was 2.2 mm Hg with 95% limits of agreement ranging from -34.2 to 38.6 mm Hg. DE estimates of PASP were determined to be inaccurate in 50.6% of patients. In part two, there was moderate correlation between DE and RHC measurements of PASP (r = 0.71, P < .01). However, despite simultaneous DE and RHC measurements, the bias for DE estimates of PASP was 8.0 mm Hg with 95% limits of agreement ranging from -28.4 to 44.4 mm Hg. CONCLUSIONS DE estimates of PASP are inaccurate in patients with PH and should not be relied on to make the diagnosis of PH or to follow the efficacy of therapy.

Prognostic Importance of Pathophysiologic Markers in Patients With Heart Failure and Preserved Ejection Fraction

Background— Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown. Methods and Results— We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area change, and 34% had RV hypertrophy. During a median follow-up time of 18 months, 102 (24%) were hospitalized for HF and 175 (42%) experienced the composite end point of cardiovascular hospitalization or death. Decreased LV compliance, measured as reduced LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg (EDV20), and RV remodeling, as indicated by increased RV wall thickness, were the 2 pathophysiologic markers most predictive of worse outcomes: adjusted hazard ratio per 1 SD decrease in EDV20=1.39 (95% confidence interval [CI], 1.10–1.75; P=0.006), and hazard ratio per 1 SD increase in RV wall thickness=1.37 (95% CI, 1.16–1.61; P<0.001). These associations persisted after additional adjustment for markers of HF severity. By contrast, markers of LV relaxation, longitudinal LV systolic dysfunction, and ventricular-arterial coupling were not significantly associated with adverse outcomes. Conclusions— In patients with HFpEF, reduced LV compliance and RV remodeling are the strongest pathophysiologic predictors of adverse outcomes.

Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension.

BACKGROUND Accurate measurement of left ventricular filling pressure is important to distinguish between category 1 pulmonary arterial hypertension (PAH) and category 2 pulmonary hypertension (PH) from left heart diseases (PH-HFpEF). We hypothesized that the common practice of relying on the digitized mean pulmonary capillary wedge pressure (PCWP-digital) results in erroneous recordings, whereas end-expiratory PCWP measurements (PCWP-end Exp) provide a reliable surrogate measurement for end-expiratory left ventricular end-diastolic pressure (LVEDP-end Exp-end Exp). METHODS We prospectively performed left and right cardiac catheterization on 61 patients referred for evaluation of PH and compared the LVEDP-end Exp to end-expiration to the (a) PCWP-end Exp and (b) PCWP-digital. RESULTS The PCWP-end Exp was a more reliable reflection of LVEDP-end Exp (mean 13.2 mm Hg vs 12.4 mm Hg; P, nonsignificant) than PCWP-digital (mean 8.0 mm Hg vs 12.4 mm Hg, P < .05). Bland-Altman analysis of PCWP-digital and LVEDP-end Exp revealed a mean bias of -4.4 mm Hg with 95% limits of agreement of -11.3 to 2.5 mm Hg. Bland-Altman analysis of PCWP-end Exp and LVEDP-end Exp revealed a mean bias of 0.9 mm Hg with 95% limits of agreement of -5.2 to 6.9 mm Hg. If PCWP-digital were used to define LVEDP-end Exp, 14 (27%) of 52 patients would have been misclassified as having PAH rather than PH-HFpEF. Patients with obesity and hypoxia were particularly more likely to be misclassified as PAH instead of PH-HFpEF if PCWP-digital was used to define LVEDP-end Exp (odds ratio 8.1, 95% CI 1.644-40.04, P = .01). CONCLUSIONS The common practice of using PCWP-digital instead of PCWP-end Exp results in a significant underestimation of LVEDP-end Exp. In our study, this translated to nearly 30% of patients being misclassified as having PAH rather than PH from HFpEF.

The Effect of Diluent pH on Bloodstream Infection Rates in Patients Receiving IV Treprostinil for Pulmonary Arterial Hypertension

BACKGROUND Recent studies have reported an increase in catheter-related bloodstream infections (BSIs) and gram-negative BSIs among patients with pulmonary arterial hypertension treated with IV treprostinil. One possible explanation is the neutral pH of the treprostinil diluent compared with the basic pH of epoprostenol. We hypothesized that administering IV treprostinil with epoprostenol diluent will lower the rate of gram-negative BSI. METHODS We prospectively enrolled patients treated with IV treprostinil and changed the diluent from native diluent to epoprostenol diluent. We compared the incidence of BSI and gram-negative BSI between those receiving IV treprostinil with epoprostenol diluent (n = 25) and those actively receiving IV epoprostenol (n = 61), as well as with a cohort of patients who received IV treprostinil in native diluent (n = 34). Incidence rates of BSI were expressed as a fraction of 1,000 medicine treatment days. RESULTS There were similar rates of BSI in those treated with treprostinil with epoprostenol diluent and those treated with epoprostenol (0.32 of 1,000 vs 0.40 of 1,000; P = .79). Also, there were similar rates of gram-negative BSI in these two cohorts (0.08 of 1,000 vs 0.20 of 1,000; P = .46). BSI rates were not statistically different between those treated with treprostinil with epoprostenol diluent and those treated with treprostinil (0.32 of 1,000 vs 0.90 of 1,000; P = .06). However, gram-negative BSIs were significantly lower in patients treated with treprostinil with epoprostenol diluent than in those treated with treprostinil (0.08 of 1,000 vs 0.71 of 1,000, respectively; P = .01). CONCLUSIONS Patients treated with treprostinil with epoprostenol diluent have a lower incidence of gram-negative BSI than do those treated with treprostinil and a similar rate to those treated with epoprostenol. Changing the diluent of treprostinil to epoprostenol diluent, in combination with the use of water-tight seals throughout the delivery system, appears to be an effective safety measure.

QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension

BACKGROUND In rodent models of pulmonary hypertension (PH) and right ventricular hypertrophy (RVH), the QTc interval is prolonged, reflecting downregulation of repolarizing Kv channels in RV myocytes. The significance of QTc prolongation in human PH is unknown. We hypothesized that QTc prolongation occurs in human PH, is associated with RVH and decreased RV function, and predicts adverse prognosis. METHODS Patients receiving a PAH-specific therapy (a prostanoid, endothelin-receptor antagonist and/or a phosphodiesterase-5 inhibitor), who had a 12-lead electrocardiogram (ECG) (n=202) were compared to age- and sex-matched controls (n=100). The duration of QTc on ECG was correlated with invasive hemodynamics (n=156) and with the status of the RV, as measured by Brain Natriuretic Peptide (NT-proBNP, n=145) and magnetic resonance imaging (n=24). Survival of the entire PH cohort and a subgroup with WHO Groups 1 and 4 PAH was prospectively determined from the Social Security Death Index. RESULTS QTc intervals were longer in PH vs. controls (454.8 ± 29 ms vs. 429.8 ± 18 ms, p<0.001) and did not differ based on PAH-specific therapy. NT-proBNP increased proportionately with QTc and was higher for those in the upper quintile (QTc ≥ 480 ms) vs. those with QTc<480 ms (4004 ± 6682 pg/mL vs. 1501 ± 1822 pg/mL, p<0.001). The QTc interval also correlated directly with increasing RV end-diastolic volume (r=.67, p<0.001) and mass (r=.0.51, p<0.05), and inversely with RV ejection fraction (r=-.49, p<0.05). In the entire PH cohort and WHO Groups 1 and 4 subgroup, QTc ≥ 480 ms and cardiac index were independent predictors of mortality. CONCLUSIONS QTc prolongation in PH patients reflects the status of the RV and is an independent predictor of mortality.

Clinical Diagnosis of Pulmonary Hypertension

There has been an increased recognition of pulmonary hypertension (PH) in clinical practice over the past 30 years. It is likely that this rise in PH diagnoses is attributable to multiple factors, including increased awareness by clinicians, the routine use of diagnostic tools such as Doppler echocardiography, and the availability and marketing of the many PH-specific drugs.1 Although the increased awareness of the disease should be viewed as a favorable development, the unintended consequences include overdiagnosis, misclassification, and at times indiscriminate use of expensive, PH-specific drugs. In this review, we address the epidemiology, prognosis, and updated clinical classification of PH. We then focus on the diagnostic approach to the patient with suspected PH with an emphasis placed on highlighting key pearls for the clinician to consider. Finally, we review an evolving conceptual framework of viewing the pulmonary vasculature and the right ventricle as a single, coupled cardiopulmonary unit. The exact prevalence of PH in both the United States and the world is not known. The most common cause of PH in the United States is left heart failure (including both heart failure with preserved and reduced systolic function) and, depending on the definition of PH used, PH may be present in upwards of 83% of patients with heart failure.2 Pulmonary arterial hypertension (PAH) on the other hand remains a generally rare disease with estimates of prevalence ranging from between 5 to 15 cases per 1 million adults.3,4 Clinical practice suggests that there has been an evolution in the phenotype of patients referred to specialty centers for the diagnosis and management of PH of all types, including PAH. Registries have provided important information about the epidemiology and changes in the PAH phenotype that have been observed over the past decades. These include changes in age, sex, …

Noninvasive cardiac output measurements in patients with pulmonary hypertension

Pulmonary hypertension (PH) is characterised by a progressive decline in cardiac output (CO) and right heart failure. NICOM® (noninvasive cardiac output monitor) is a bioreactance-based technology that has been broadly validated, but its specific application in right heart failure and PH is unknown. Cardiac catheterisation was performed in 50 consecutive patients with PH. CO measurements were performed using three different methods (thermodilution, Fick and NICOM) at baseline and after vasodilator challenge. We compared the precision (coefficient of variation) and accuracy of NICOM compared to thermodilution and Fick. The mean CO (L·min−1) at baseline as measured by the three methods was 4.73±1.15 (NICOM), 5.69±1.74 (thermodilution) and 4.84±1.39 (Fick). CO measured by NICOM was more precise than by thermodilution (3.5±0.3% versus 9.6±6.1%, p<0.001). Bland–Altman analyses comparing NICOM to thermodilution and Fick revealed bias and 95% limits of agreement that were comparable to those comparing Fick to thermodilution. All three CO methods detected an increase in CO in response to vasodilator challenge. CO measured via NICOM is precise and reliably measures CO at rest and changes in CO with vasodilator challenge in patients with PH. NICOM may allow for the noninvasive haemodynamic assessment of patients with PH and their response to therapy.

Prior Aspirin Use and Outcomes in Acute Coronary Syndromes

OBJECTIVES The purpose of this study was to determine whether patients taking aspirin before an acute coronary syndrome (ACS) are at higher risk of recurrent events or mortality. BACKGROUND Controversy exists whether prior aspirin use is an independent predictor of worse outcomes in patients who experience an ACS. METHODS We evaluated 66,443 ACS patients from a merged database of previous Thrombolysis in Myocardial Infarction trials. We evaluated the differences in ACS type, total mortality, and the composite end point of death, myocardial infarction (MI), recurrent ischemia, or stroke between prior aspirin and nonprior aspirin users. We used multivariate analysis to control for differences in baseline characteristics. RESULTS Prior aspirin users (n = 17,839) were older (63 years vs. 59 years) and had more coronary risk factors and evidence of coronary artery disease (MI, angina, prior intervention) than nonprior aspirin users (n = 48,604) (all p < 0.0001). Prior aspirin use was associated with less severe types of ACS at presentation (e.g., unstable angina > non-ST-segment elevation MI > ST-segment elevation MI) than their nonaspirin user counterparts (p < 0.0001). After multivariate analysis, there was no difference in total mortality between prior aspirin users and nonaspirin users at day 30 (odds ratio [OR]: 1.01; 95% confidence interval [CI]: 0.90 to 1.13) or by the last follow-up visit (mean 328 days) (hazard ratio: 1.03; 95% CI: 0.95 to 1.11). Prior aspirin use was modestly associated with recurrent MI (OR: 1.26; 95% CI: 1.12 to 1.43) and the composite end point (OR: 1.16; 95% CI: 1.08 to 1.24). CONCLUSIONS Prior aspirin use was associated with more comorbidities and coronary disease and a higher risk of recurrent MI, but not mortality. As such, it should best be considered a marker of a patient population at high risk for recurrent adverse events after ACS.

Modified HeartMate II driveline externalization technique significantly decreases incidence of infection and improves long-term survival.

Driveline (DL) infection has been a major source of morbidity and mortality following HeartMate II left ventricular assist device (LVAD) implant, despite a significantly lower incidence compared with pulsatile flow devices. The purpose of this study was to compare the incidence of DL infection using two different externalization techniques. Between July 1, 2008, and October 15, 2011, 125 consecutive patients underwent HeartMate II LVAD implant at a single institution. Patients that underwent implant in 2008–2009 (n = 45) had the velour portion of the DL externalized (Velour group) and those that were implanted in 2010–2011 (n = 80) had only the silicone portion externalized (Silicone group). Kaplan–Meier analysis with log-rank test was used to compare actuarial DL infection-free survival and a composite of death and DL infection-free survival. There were 20/45 (44.4%) DL infections in the Velour group compared with 7/80 (8.8%) in the Silicone group. Driveline infection-free survival was significantly better for the Silicone versus Velour group as was the composite end-point of death and infection-free survival (p < 0.001). Externalization of only the silicone portion of the DL led to a dramatic reduction in infections and significantly improved survival after implant. This represents an opportunity to decrease the incidence of this important cause of morbidity and mortality after LVAD implant.

Right Ventricular Failure in Patients with Left Ventricular Assist Devices

Right ventricular (RV) failure that develops following LVAD placement is an important and challenging complication that occurs in approximately 15-25% of LVAD patients. Thus, a thorough evaluation that identifies pre-operative clinical predictors of RV failure is crucial to aid in the appropriate treatment and prognostication. Following LVAD implant, three major physiologic changes invariably occur that will influence RV function: an increase in RV preload, a decrease in RV afterload, and an alteration in RV contractility. Management strategies exist to minimize the likelihood and severity of RV failure post-LVAD. Further studies are needed that also focus on intermediate and late post-LVAD RV failure.